Candidate: The candidate is a board certified radiation oncologist with training in clinical radiation oncology, yeast genetics and DNA repair. My long-term goal and the goal of this proposal is to understand fundamental biologic processes, such as DNA damage, and use this understanding to improve cancer care. Environment: This project will be conducted in an extremely collaborative environment with the mentorship of recognized experts in the field of oxidative stress and metabolism. Research: The work proposed in this project will seek to determine the role of endogenous oxidative stress and damage in mediating thymineless death. Chemotherapy agents which act to deplete thymine stores have long been used to sensitize cancer to the oxidative stress of exogenously applied ionizing radiation. Thymine depletion appears particularly toxic to mitochondrial DNA. Mitochondria are a major source of reactive oxygen species (ROS) and damaged mitochondria may produce more ROS during thymine depletion. The hypothesis of this proposal is that endogenous mitochondrial oxidative stress and DNA damage contribute to the toxicity of thymine depletion. This hypothesis will be tested using the yeast Saccharomyces cerevisiae as a genetically tractable model system and confirmed where possible in human cancer cell lines. S. cerevisiae deficient in DNA repair, cell cycle responses and ROS metabolism will be tested for their sensitivity to thymine starvation. We will study survival of the cell and mitochondria using a variety of endpoints to gain insight into how mitochondrial damage may contribute to thymineless death. Relevance: Thymine deprivation is the basis of many cancer treatments. Successful completion of this project will provide novel insights into how mitochondrial metabolism and DNA repair can be used to enhance the effectiveness and selectivity of thymine deprivation based treatments. [unreadable] [unreadable] [unreadable]